Inhaled Laninamivir Octanoate as Prophylaxis for Influenza in Children Takashi Nakano, MD, PhD, a Naruhiko Ishiwada, MD, PhD, b Tokuhito Sumitani, MSc, c Mitsutoshi Uemori, MSc, d Koji Isobe, MSc, c for the Laninamivir Prophylaxis Study Group BACKGROUND: A single 20-mg dose of inhaled laninamivir octanoate is an effective treatment of abstract influenza. However, the efficacy of laninamivir octanoate for the prevention of influenza in children <10 years of age has not yet been established. METHODS: We conducted a double-blind, multicenter, randomized, placebo-controlled study to determine whether the efficacy of a single 20-mg dose of inhaled laninamivir octanoate to prevent the development of influenza was superior to that of placebo as prophylaxis for influenza in pediatric (<10 years) household members of index cases. Eligible subjects without influenza, in contact with an influenza-infected index case living in the same household, were blindly randomly assigned in a 1:1 ratio to receive 20 mg of laninamivir octanoate or placebo. The primary end point was the proportion of subjects who developed clinical influenza during a 10-day period. RESULTS: A total of 343 subjects were randomly assigned, with 341 subjects included in the full analysis set for the primary analysis. The proportions of subjects who developed clinical influenza were 11% (18/171) in the laninamivir octanoate group and 19% (33/170) in the placebo group (P = .02). The relative risk reduction was 45.8% (95% confidence interval, 7.5% to 68.2%). The incidence of adverse events was similar in both groups. CONCLUSIONS: A single 20-mg dose of inhaled laninamivir octanoate was effective and well tolerated as prophylaxis for influenza. a Department of Pediatrics, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan; bDepartment WHAT’S KNOWN ON THIS SUBJECT: Neuraminidase of Infectious Diseases Medical Mycology Research Center, Chiba University, Chiba, Japan; and cClinical inhibitors (NAIs) are recommended for d Development Department and Clinical Data and Biostatistics Department, Daiichi Sankyo Co, Ltd, Tokyo, Japan chemoprophylaxis of infl uenza. But only a few Drs Nakano and Ishiwada conceptualized and designed the study, interpreted the data, and clinical data are available on the prophylactic reviewed and revised the manuscript; Mr Isobe and Mr Sumitani conceptualized and designed the effi cacy of NAIs in children <10 years of age. study, designed the data collection instruments, supervised data collection and interpreted the WHAT THIS STUDY ADDS: This study demonstrates data, and drafted the initial manuscript; Mr Uemori performed the statistical analysis, interpreted the effi cacy of laninamivir as prophylaxis for the data, and drafted the initial manuscript; and all authors approved the fi nal manuscript as submitted. infl uenza in children aged ≥2 and <10 years with a single 20-mg dose of inhaled laninamivir octanoate. DOI: 10.1542/peds.2016-0109 Accepted for publication Sep 1, 2016 Address correspondence to Laninamivir Prophylaxis Study Group, Clinical Development Department, Daiichi Sankyo Co, Ltd, Hiromachi 1-2-58, Shinagawa-ku, Tokyo 140-8710, Japan. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2016 by the American Academy of Pediatrics To cite: Nakano T, Ishiwada N, Sumitani T, et al. Inhaled Laninamivir Octanoate as Prophylaxis for Infl uenza in FINANCIAL DISCLOSURE: Drs Nakano and Ishiwada were consultants of this study for Daiichi Children. Pediatrics. 2016;138(6):e20160109 Sankyo; the other authors have indicated they have no fi nancial relationships relevant to this article to disclose. Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 138 , number 6 , December 2016 :e 20160109 ARTICLE Influenza is a common viral members of the household infected the index case was present within respiratory illness that could by influenza A or B virus in the the household, had a history of increase risks of hospitalization, 2011/2012 influenza season) has abnormal behavior accompanied by severe morbidity, and death 1 – 3 in been demonstrated. 16 influenza or pyrexia, hypersensitivity young children, elderly, and others However, the efficacy of laninamivir to neuraminidase inhibitors (NAIs), with underlying medical conditions. octanoate as prophylaxis for being treated with corticosteroid Additionally, abnormal behavior influenza in children <10 years of or other immunosuppressant, in children has been reported in age has not yet been evaluated. We or had been treated with a NAI 4–6 patients with influenza. It is conducted a randomized controlled within 4 weeks before informed highly important to take preventive study to determine whether consent. Influenza inactivated- measures against seasonal influenza, laninamivir octanoate is efficaciously vaccine recipients in the 2014/2015 particularly in the pediatric superior compared with placebo, season were considered eligible population. Prophylactic vaccination in pediatric (<10 years of age) because prophylaxis for influenza against influenza has been generally household members of an index case is particularly indicated for groups recommended for children, and as a prophylaxis of influenza. at risk for complications, and hence vaccination rates among children for whom influenza vaccination is had reached 40% to 60% during recommended. the 6 seasons of 2005/2006 to METHODS 2010/2011.7 However, despite the increasing rates in influenza Study Design Study Procedure vaccination, an outbreak of 2009 This study was a randomized, pandemic influenza A (H1N1) double-blind, placebo-controlled trial Participants were blindly randomly [A(H1N1)pdm09] virus occurred, and conducted from November 2014 to assigned in a 1:1 ratio to receive oseltamivir-resistant strains emerged March 2015 at 50 pediatric clinics in 20 mg of inhaled laninamivir in the years after the pandemics. 8 Japan. The study was approved by octanoate or placebo through an Furthermore, during the 2013/2014 the ethics committee at each center inhaler on day 1. The study used season in Japan, influenza A(H1N1) and complied with the provisions random allocation through an pdm09 virus cross-resistant to of Good Clinical Practice and the interactive Web response system oseltamivir and peramivir was Declaration of Helsinki. 17 All index that centrally assigned subjects on detected. 9 Such circumstances cases, subjects, and their legally the basis of computer-generated suggest the emergence and outbreak acceptable representatives provided permuted-block randomization by of new drug-resistant strains of written or oral informed consent Bell Medical Solutions, Inc (Tokyo, influenza virus. Given the limitations in accordance with their age before Japan). Stratification factors for of vaccination, extensive variations enrollment in the study. 18 randomization were virus types in the option for antiinfluenza for the index cases and influenza prophylaxis are desirable as an Subjects vaccination status of the 2014/2015 adjunct to influenza vaccine. Eligible subjects were aged <10 influenza season for the subjects. years, had an axillary temperature After confirming eligibility, the Laninamivir potently inhibits of ≤36.9°C, had no influenzalike investigator enrolled the subjects neuraminidase activities of various symptoms at the time of receiving through the Web system, which influenza A and B viruses, including consent, and were determined by generated allocation numbers subtypes N1 to N9, influenza the investigator of having sufficient for the drug. The subjects, index A(H1N1)pdm09 viruses, highly inhalation capability for using an cases, investigators, and trial pathogenic avian influenza H5N1 inhaler (evaluated by a test using personnel were blinded to the viruses, and oseltamivir-resistant training whistles 19). Eligible index group assignment throughout the viruses. 10, 11 The efficacy of a single cases were the first members trial. If the subjects were deemed 20-mg dose of laninamivir octanoate infected with influenza A or B virus ineligible after obtaining informed for influenza treatment in adults and in the 2014/2015 influenza season consent, they were not enrolled. children has been demonstrated. 12 – 15 within the household, tested positive The investigator recorded whether In addition, the efficacy of a single for influenza by the rapid diagnostic subjects inhaled the drug well or not. 20-mg dose of laninamivir octanoate test. The study excluded subjects who The index cases were treated with once daily for 2 days as postexposure were unable to start the treatment oseltamivir or zanamivir. Participants prophylaxis of influenza in household within 48 hours of the onset of were not allowed to use any other members (adults and children ≥10 influenza symptom in the index case, antiinfluenza agents before the years of age) of index cases (first infected family members other than diagnosis of influenza infection. Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 NAKANO et al Clinical and Virological Monitoring end points included the proportions after enrollment. All analyses were of subjects with symptomatic performed by using SAS System The legal representatives influenza (laboratory-confirmed Release 9.2 (SAS Institute, Inc, Cary, observed and recorded the axillary influenza with either an axillary NC). The planned sample size was temperature and the presence or temperature of ≥37.5°C or ≥1 300 subjects on the basis